Cherie B. Nau

Effects of AGN 192024, a new Ocular Hypotensive agent, on aqueous dynamics

PURPOSE To determine the mechanism of intraocular pressure lowering for the Ocular Hypotensive Lipid, AGN 192024 (Allergan, Inc, Irvine, California). METHODS Twenty-five normal human volunteers between the ages of 21 and 48 took part in a randomized, double-masked, placebo-controlled, paired-comparison study in which intraocular pressure, aqueous humor flow, and tonographic resistance to outflow were studied. Measurements of aqueous flow were made during the day and at night while subjects slept. Intraocular pressure was measured with the Goldmann tonometer, and resistance to outflow was measured by electronic recording Schiötz tonography. RESULTS Intraocular pressure was decreased by 20% on day 3 in AGN 192024-treated eyes in comparison with placebo-treated eyes in normal subjects (P <.001). Aqueous humor flow was stimulated 13% during the day (P =.007) and 14% at night (P =.014) by the drug. Tonographic resistance to outflow was decreased 26% by AGN 192024 (P <.001), and apparent resistance to outflow (the ratio of intraocular pressure to aqueous flow) was decreased 31% (P <.001). Assuming that AGN 192024 does not cause prolonged lowering of episcleral venous pressure, the results show that pressure-insensitive outflow is enhanced by 50%, whereas tonographic facility of outflow (reciprocal of resistance) was enhanced 35%. CONCLUSIONS AGN 192024 is an ocular hypotensive agent that works by enhancing both pressure-sensitive and pressure-insensitive aqueous humor outflow without diminishing aqueous humor formation.

Mechanism of Action of Bimatoprost, Latanoprost, and Travoprost in Healthy Subjects: A Crossover Study

PURPOSE To study the effects of 3 prostaglandin analogs, bimatoprost, latanoprost, and travoprost, on aqueous dynamics in the same subjects and to compare techniques of assessing outflow facility. DESIGN Experimental study (double-masked, placebo-controlled, randomized paired comparison, 4-period crossover). PARTICIPANTS Thirty healthy adult subjects. METHODS Bimatoprost, latanoprost, travoprost, or a placebo was administered to the left eye once a day in the evening for 7 days, after a minimum 4-week washout period between each session. Tonographic outflow facility was measured by Schiøtz tonography and pneumatonography on day 7. On day 8, the aqueous humor flow rate and fluorophotometric outflow facility were measured by fluorophotometry. Uveoscleral outflow was calculated from the aqueous humor flow rate and outflow facility using the Goldmann equation. MAIN OUTCOME MEASURES Facility of outflow, aqueous humor flow rate, intraocular pressure (IOP), and calculation of uveoscleral outflow. RESULTS All medications lowered IOP relative to a placebo. None of the drugs affected aqueous humor production. All medications increased outflow facility compared with placebo when measured by Schiøtz and 2-minute pneumatonography (P< or =0.02); the apparent increase of outflow facility measured with fluorophotometry and 4-minute pneumatonography did not reach statistical significance. In contrast, uveoscleral outflow was significantly increased by all medications when calculated from 4-minute pneumatonography data, and fluorophotometry and Schiøtz data at higher episcleral venous pressures. The apparent increase found with 2-minute pneumatonography did not reach statistical significance. These differing results in the same patients indicate that differences in measurement techniques, and not differences in mechanism of action, explain previous conflicting published reports on the mechanism of action of the prostaglandins. CONCLUSIONS Bimatoprost, latanoprost, and travoprost have similar mechanisms of action. All 3 drugs reduce IOP without significantly affecting the aqueous production rate. All drugs increase aqueous humor outflow, either by enhancing the pressure-sensitive (presumed trabecular) outflow pathway or by increasing the pressure-insensitive (uveoscleral) outflow, but the assessment of the amount of flow through each pathway depends upon the measurement technique.

Keratocyte density in keratoconus. A confocal microscopy study

PURPOSE To estimate keratocyte density in human corneas with keratoconus by confocal microscopy. DESIGN Prospective, observational cohort study. METHODS Twenty-nine unscarred corneas of 19 patients with keratoconus and 29 corneas of 19 controls matched for age (+/-3 years) and contact lens wear were examined by using confocal microscopy. Images were recorded from the full-thickness central cornea. A masked observer manually counted bright objects (keratocyte nuclei) in images without motion blur. Cell densities in anteroposterior stromal layers of keratoconus corneas were compared with densities in corresponding layers of control corneas. RESULTS In keratoconus patients, age 40 +/- 15 years (mean +/- standard deviation), keratocyte density was 19% lower in those who wore contact lenses (16,894 +/- 4032 cell/mm(3), n = 12) than in those who did not wear contact lenses (20,827 +/- 4934 cell/mm(3), n = 17, P =.03). In control patients, age 39 +/- 16 years, there was no difference in keratocyte density between those who wore contact lenses (n = 12) and those who did not wear contact lenses (n = 17, P =.80). Among contact lens wearers, keratocyte density was 25% lower in keratoconus corneas (16,894 +/- 4, 032 cell/mm(3), n = 12 [9 = rigid gas-permeable lenses, 3 = soft lenses]) than in control corneas (22,579 +/- 2, 387 cell/mm(3), n = 12 [3 = rigid gas-permeable lenses, 9 = soft lenses], P =.002), the result of cell density being lower in the most anterior keratocyte layer (P =.001) and the layers between 0% to 10% (P <.001), 67% to 90% (P <.001), and 91% to 100% (P <.001) of stromal thickness. Among noncontact lens wearers, there was no difference in cell density between keratoconus and controls (P =.41). CONCLUSION Keratocyte density is decreased in the anterior and posterior stroma of keratoconus patients who wear contact lenses.

Circadian variation of aqueous dynamics in young healthy adults.

PURPOSE Recent research indicates that intraocular pressure (IOP) does not decrease significantly during the nocturnal period, although aqueous humor flow decreases by 50% or more at night. This study was undertaken to investigate whether changes in outflow facility, episcleral venous pressure, or uveoscleral flow at night could account for the nocturnal IOP. METHODS Sixty-eight eyes of 34 healthy subjects (age, 18-44 years; mean, 29) were studied. Aqueous humor flow rate, IOP, and outflow facility were measured with pneumatonometry, anterior chamber fluorophotometry, and Schiotz tonography respectively, in each eye during the mid-diurnal (2-4 PM) and mid-nocturnal (2-4 AM) periods. Nocturnal IOP, flow rate, and outflow facility were compared to the same variables during the diurnal period. Mathematical models based on the modified Goldmann equation were used to assess the conditions under which these results could be reconciled. RESULTS Supine IOP decreased slightly from 18.9 +/- 2.7 mm Hg in the mid-diurnal period to 17.8 +/- 2.5 mm Hg in the mid-nocturnal period (mean +/- SD, P = 0.001). Aqueous flow rate decreased from 2.26 +/- 0.73 to 1.12 +/- 0.75 microL/min (mean +/- SD, P < 0.001). There was a nonsignificant trend toward a nocturnal decrease of outflow facility (diurnal, 0.27 +/- 0.11 microL/min/mm Hg; nocturnal, 0.25 +/- 0.08 microL/min/mm Hg; mean +/- SD, P = 0.13). CONCLUSIONS Outflow facility measured by tonography does not decrease enough during the nocturnal period to compensate for the decreased aqueous humor flow rate. Modeling results indicate that the experimental results could be reconciled only if nocturnal changes in episcleral venous pressure and/or uveoscleral flow occurred.

Comparison of corneal endothelial cell images from a noncontact specular microscope and a scanning confocal microscope

Purpose: We compared endothelial cell density (ECD) from images recorded by the ConfoScan 3 confocal microscope and a noncontact specular microscope. Methods: Endothelial micrographs of 50 normal corneas of 25 subjects were acquired by a Konan Noncon Robo noncontact specular microscope (Konan Medical, Inc., Hyogo, Japan) and a ConfoScan 3 confocal microscope (Nidek Technologies, Inc, Greensboro, NC). ECD was determined in images from both instruments by using the HAI CAS System Corners Method (HAI Labs, Inc., Lexington, MA). Distances in the images from both machines were calibrated from images of an external scale. Images from the ConfoScan 3 were also assessed using the automated endothelial analysis software provided by the manufacturer, with and without manual correction. Results: The ECD was 2634 ± 186 cells/mm2 (mean ± SD) and 2664 ± 173 cells/mm2 by the Robo and ConfoScan 3 Corners methods, respectively. Differences between these 2 methods were not significant. When the automated analysis software was used, however, significant differences were found (P = 0.001). The uncorrected analysis program provided with the ConfoScan 3 indicated a higher ECD (2742 ± 284 cells/mm3) than the Corners method did with images from the Robo and ConfoScan 3. The ECD from the manually corrected ConfoScan 3 method was 2716 ± 229 cells/mm3, not significantly different from the ConfoScan 3 Corners method but significantly different from the Robo Corners method. Conclusions: The ConfoScan 3 can be used interchangeably with the Robo when the Corners method is used to assess ECD and the magnification of both microscopes is calibrated with an external scale. If the proprietary software provided with the ConfoScan 3 is used, it should be manually corrected.

Graft Thickness, Graft Folds, and Aberrations after Descemet Stripping Endothelial Keratoplasty for Fuchs Dystrophy

PURPOSE To determine whole-eye high-order aberrations (HOAs) in pseudophakic eyes after Descemet stripping endothelial keratoplasty (DSEK) for Fuchs dystrophy, and to establish relationships between graft thickness, HOAs, and visual acuity. DESIGN Cross-sectional study. METHODS Whole-eye HOAs were measured in pseudophakic eyes at intervals through 24 months after DSEK, and in otherwise healthy pseudophakic control eyes implanted with the same type of spherical intraocular lens. Wavefront errors were assessed by a Hartmann-Shack aberrometer over a 4-mm-diameter optical zone. In DSEK eyes, central graft thickness and stromal graft folds were measured using confocal microscopy in vivo, and best-corrected visual acuity (BCVA) was determined by the electronic Early Treatment of Diabetic Retinopathy Study method. RESULTS Total HOAs at 24 months after DSEK (0.28 ± 0.11 μm, mean ± SD, n = 17) were higher than those in pseudophakic controls (0.16 ± 0.07 μm, n = 25, P < .001); specifically, trefoil and quadrafoil were higher after DSEK. At 24 months, total HOAs (r = 0.69, P < .001) and graft folds (r = 0.41, P = .02) were correlated with central graft thickness, and BCVA was correlated with total HOAs (r = 0.39, P = .01) but not with graft thickness (r = -0.24, P = .20, n = 27). CONCLUSIONS Whole-eye HOAs are higher after DSEK compared to untreated corneas. Thicker grafts are associated with increased HOAs and more graft folds, suggesting that the donor lenticule contributes, in part, to the wavefront errors. Although BCVA is weakly related to total HOAs after DSEK, it is not related to graft thickness.

Effects of glaucoma medications on corneal endothelium, keratocytes, and subbasal nerves among participants in the ocular hypertension treatment study

Purpose: To compare subbasal corneal nerve and keratocyte density and endothelial characteristics of ocular hypertensive patients treated with medications or observation. Methods: Participants in the Ocular Hypertensive Treatment Study (OHTS) randomized at Mayo Clinic to medication or observation were evaluated with specular microscopy annually for 6 years. Confocal microscopy was performed 78 to 108 months after enrollment. Subbasal nerve density was calculated by manual tracing and digital image analysis. Keratocyte density was determined by manual counting methods. Data were compared using a t test and a rank sum test. Results: After 6 years, corneal endothelial cell density, percent hexagonal cells, and coefficient of variation of cell area for the observation (n = 21) and medication groups (n = 26) were similar (2415 ± 300 vs. 2331 ± 239 cells/mm2; 63% ± 11% vs. 65% ± 10%; and 0.32 ± 0.07 vs. 0.30 ± 0.06, respectively). Of 38 participants undergoing confocal examination, the medication group (n = 19) had fewer nerves (3.8 ± 2.1 vs. 5.9 ± 2.0 nerves/frame; P = 0.02) and a lower nerve density (5643 ± 2861 vs. 9314 ± 3743 μm/mm2; P = 0.007) than the observation patients (n = 10). An additional 9 patients in the observation group, who began medication before confocal scanning, had intermediate nerve densities. Full-thickness keratocyte density was similar, with 22,257 ± 2419 and 23,430 ± 3285 cell/mm3 in the observation and medication groups, respectively. Conclusions: Chronic administration of glaucoma medications causes a decrease in the number and density of corneal subbasal nerve fiber bundles but does not affect keratocyte density or corneal endothelial characteristics.

Measuring corneal thickness with the ConfoScan 4 and z-ring adapter.

Purpose. To assess the precision and accuracy of the z-ring adapter with the ConfoScan 4 confocal microscope for measuring corneal thickness. Methods. Thirty healthy corneas of 15 volunteers were scanned twice with a ConfoScan 4 confocal microscope equipped with a z-ring adapter (Nidek, Inc., Fremont, CA) and with a Tandem Scanning confocal microscope (Tandem Scanning Corporation, Reston, VA). Corneal thickness was determined from the position of the focal plane at the epithelial and endothelial surfaces. Distances measured by both instruments were calibrated from scans of 15 polymethylmethacrylate contact lenses with known thicknesses between 400 and 650 &mgr;m. Corneal thickness was also measured by ultrasonic pachymetry (DGH Technologies, Inc., Exton, PA). Results. Corneal thickness measured with the ConfoScan 4 (mean, 529 ± 35 &mgr;m) was not significantly different from thickness measured with the Tandem Scanning confocal microscope (mean, 531 ± 30 &mgr;m) (P=0.30). The mean difference between the first and second scans was 1.1 ± 20 &mgr;m and –2.6 ± 17 &mgr;m with the ConfoScan 4 and Tandem Scanning microscopes, respectively. Both confocal microscopes indicated thinner corneas than ultrasonic pachymetry did (567 ± 35 &mgr;m) (P<0.0001). Conclusions. Mean corneal thickness measured with the z-ring adapter with the ConfoScan 4 agrees with mean corneal thickness measured with the Tandem Scanning confocal microscope when both instruments are correctly calibrated. Ultrasonic pachymetry indicated a mean corneal thickness that was at least 35 &mgr;m greater than was indicated by either confocal microscope.

Circadian Variation of Aqueous Humor Dynamics in Older Healthy Adults

PURPOSE Intraocular pressure in the sitting position changes minimally during sleep, although aqueous humor flow decreases by 50% or more at night. The explanation for this apparent discrepancy has been unclear. This study investigated the roles of outflow facility, episcleral venous pressure (EVP), and uveoscleral outflow in maintaining IOP at night. METHODS Forty-two eyes of 21 healthy subjects (age 47-76 years, mean 59 years) were studied. Aqueous humor flow rate, IOP in the sitting position, outflow facility, and EVP were measured in each eye during the middiurnal period (2:00-4:00 PM). Uveoscleral flow was calculated from the other variables by using the modified Goldmann equation. These variables were remeasured during the midnocturnal period (2:00-4:00 AM) and compared with those measured during the diurnal period by using generalized estimating equation models. RESULTS Intraocular pressure did not change from the middiurnal period (13.9 ± 3.0 mm Hg) to the midnocturnal period (13.0 ± 1.8 mm Hg, mean ± SD, P = 0.07), although aqueous humor flow rate decreased from 2.48 ± 0.96 μL/min to 1.27 ± 0.63 μL/min (P < 0.001). Outflow facility decreased from 0.23 ± 0.06 μL/min/mm Hg to 0.20 ± 0.06 μL/min/mm Hg (P = 0.004), and EVP was unchanged from the middiurnal period (7.4 ± 1.8 mm Hg) to the midnocturnal period (7.4 ± 2.2 mm Hg, P = 0.95). Uveoscleral outflow decreased 93%, from 0.94 ± 1.26 μL/min during the middiurnal period to 0.07 ± 0.78 μL/min (P = 0.008) during the midnocturnal period. CONCLUSIONS The nocturnal decrease in aqueous humor flow rate in older, healthy subjects is compensated by a small decrease in outflow facility and a large decrease in uveoscleral outflow to maintain a stable IOP.

Comparison of the efficacy of betaxolol-brinzolamide and timolol-dorzolamide as suppressors of aqueous humor flow in human subjects

OBJECTIVE To compare the efficacy of combinations of betaxolol-brinzolamide and timolol-dorzolamide as suppressors of aqueous humor flow and ocular hypotensive agents. DESIGN Placebo-controlled, masked comparison of the two drug combinations. PARTICIPANTS Twenty-five normal human volunteers with the fellow eye serving as control. METHODS OR TESTING: Fluorophotometric measurement of aqueous humor flow and pneumatonometric measurement of intraocular pressure. MAIN OUTCOME MEASURES Aqueous humor flow and intraocular pressure. RESULTS The betaxolol-brinzolamide combination lowered aqueous flow 39% to 44%, and the timololdorzolamide combination lowered aqueous flow 51%. The betaxolol-brinzolamide combination lowered intraocular pressure 14% to 19%, and the timolol-dorzolamide combination lowered it 18% to 24%. CONCLUSIONS Both drug combinations were effective; the timolol-dorzolamide combination appeared to be the more effective of the two after short-term exposure (24 hours).